ABSTRACT/SUMMARY The United States is experiencing an epidemic of drug overdose deaths, most attributable to some type of opioid. Opioid overdose deaths are surging because of increasing non-medical use of prescription opioids combined with an increasingly available and cheaper alternative: heroin with or without admixed fentanyl. Naloxone is an effective and safe opioid antagonist that reverses the potentially fatal respiratory and/or central nervous system depression caused from opioid overdose. While naloxone is effective in reducing the risk of overdose death, it does not address the underlying opioid use disorder or the hazards of opioid administration by people who inject drugs, and therefore people who are injecting or who may do so in the future are at high risk of contracting HIV and hepatitis C. Linking interventions to naloxone distribution, such as medical assisted therapy to treat opioid use disorder (e.g., methadone or buprenorphine), HIV pre-exposure prophylaxis (PreP), and hepatitis C screening, has the potential to prevent new infections and their sequela and avoid costly treatments. However, the high cost of PreP and hepatitis C treatment magnifies the importance of employing these interventions successfully and with favorable value. In order to weigh these tradeoffs systematically and to inform future overdose prevention programs we seek to employ a decision analytic model to compare alternative strategies for linking naloxone distribution with medical assisted therapy, HIV prevention, and HCV screening. Accordingly, our Aims compare alternative scenarios for treating OUD and preventing overdose, HIV infection, and HCV infection, to compare life expectancy, quality-adjusted life expectancy (QALY), and value. Our proposal extends our fruitful collaboration with the CT DPH and initiates a new collaboration with the VA DPH, emphasizing policy options that build on existing infrastructure, in particular OEND, Syringe Exchange Programs (SEP) where applicable, and settings for MAT. We analyze separately strategies directed at persons who use opioids (Aim 1) and strategies directed at overdose responders (Aim 2) because these strategies are often distinctly advocated, funded, administered, and implemented.